Sulfur mustard (SM) is a highly toxic blister agent which has been used many times in several wars and conflicts and caused heavy casualties. Ease of production and lack of effective therapies make SM a potential threat to public health. SM intoxication causes severe damage on various target organs, such as the skin, eyes, and lungs. In addition, SM exposure can also lead to hepatotoxicity and severe liver injuries. However, despite decades of research, the molecular mechanism underlying SM-induced liver damage remains obscure. SM can be converted into various products via complex hepatic metabolism in vivo. There are some pieces of evidence that one of the oxidation products of SM, divinyl sulfone (DVS), exhibits even more significant toxicity than SM. Nevertheless, the molecular toxicology of DVS is still hardly known. In the present study, we confirmed that DVS is even more toxic than SM in the human hepatocellular carcinoma cell line HepG2. Further mechanistic study revealed that DVS exposure (200 μM) promotes pyroptosis in HepG2 cells, while SM (400 μM) mainly induces apoptosis. DVS induces gasdermin D (GSDMD) mediated pyroptosis, which is independent of caspases activation but depends on the large amounts of reactive oxygen species (ROS) and severe oxidative stress produced during DVS exposure. Our findings may provide novel insights for understanding the mechanism of SM poisoning and may be helpful to discover promising therapeutic strategies for SM intoxication.

芥子气（SM）是一种剧毒起泡剂，在多次战争和冲突中多次使用并造成重大人员伤亡。生产的简便性和缺乏有效的治疗方法使 SM 对公众健康构成潜在威胁。 SM中毒会对皮肤、眼睛和肺部等多种靶器官造成严重损害。此外，SM暴露还可导致肝毒性和严重肝损伤。然而，尽管经过数十年的研究，SM 引起的肝损伤的分子机制仍然不清楚。 SM在体内可通过复杂的肝脏代谢转化为各种产物。有一些证据表明 SM 的氧化产物之一二乙烯基砜 (DVS) 表现出比 SM 更显着的毒性。尽管如此，DVS 的分子毒理学仍然鲜为人知。在本研究中，我们证实 DVS 在人肝癌细胞系 HepG2 中的毒性甚至比 SM 还要大。进一步的机制研究表明，DVS暴露（200μM）促进HepG2细胞焦亡，而SM（400μM）主要诱导细胞凋亡。 DVS 可诱导gasdermin D (GSDMD) 介导的焦亡，该焦亡与半胱天冬酶的激活无关，但取决于 DVS 暴露期间产生的大量活性氧 (ROS) 和严重的氧化应激。我们的研究结果可能为理解 SM 中毒的机制提供新的见解，并可能有助于发现有前景的 SM 中毒治疗策略。